Catalytic Oxidative Fragment Coupling Reactions

 描述（由申请人提供）：本提案的总体目标是设计独特的工艺，用于通过C-H活化化学形成C-C、C-O和C-N键来氧化偶联片段。催化剂库将设计用于仿生反应的研究，使用两个指导原则：1）将催化剂氧化电位与所考虑的底物的氧化电位相匹配，2）选择可以利用的金属 氧气以再生催化物质。这些库将部署在一个高通量的微型格式，发现迄今为止无法想象的反应模式在五个领域：苯酚耦合，苯胺耦合，交叉耦合的烯醇底物与富电子的芳香族化合物，烯基苯酚耦合，和其他耦合/氧化。从所获得的数据，反应“配置文件”将被构建和新的推论有关的反应性，选择性，和机制， 这将被实验验证。这一提议的根本标志是能够获得新的反应模式，以有效和合理的方式构建重要的有机结构。高通量的微型实验工具允许合理的假设进行广泛的询问，并促进在可能的反应空间中的许多相互依赖的变量的优化。新的氧化偶联化学的发展导致效率的提高，由于更低的步骤数和更小的废物流，因为反应位点不再需要用官能团预活化以获得选择性反应。因此，氧化活化的底物数量本质上大于非氧化偶联过程。这一领域的挑战来自于这一事实，即由于典型有机分子中存在大量C-H键，因此在任何给定转化中具有选择性。仿生过程的使用导致生物活性天然产物和天然产物样核，药物化学中的理想实体。新的合成方法大大增加了对未开发的化学空间的利用，从而产生了造福社会的材料和药物。将向研究生和其他同事提供在工业环境之外缺乏的宝贵培训。

 DESCRIPTION (provided by applicant): The overall objective of this proposal is to devise unique processes for the oxidative coupling of fragments via C-C, C-O, and C-N bond formation by means of C-H activation chemistry. Catalyst libraries will be designed for study of biomimetic reactions using the two guiding principles: 1) matching catalyst oxidation potentials with the oxidation potentials of the substrates under consideration and 2) selecting metals that can utilize oxygen to regenerate the catalytic species. These libraries will be deployed in a high-throughput microscale format to discover reactivity patterns heretofore unimagined in five areas: phenol coupling, aniline coupling, cross-coupling of enolic substrates with electron-rich aromatics, alkenyl phenol coupling, and other couplings/oxygenations. From the data obtained, reaction "profiles" will be constructed and new inferences about reactivity, selectivity, and mechanism will be made, which will be tested experimentally. The fundamental hallmark of this proposal is the ability to access new reaction patterns to construct important organic structures in an efficient and rational manner. High throughput microscale experimentation tools permit rational hypotheses to be interrogated broadly and facilitate optimization of the many interdependent variables in the possible reaction space. The development of new oxidative coupling chemistry leads to increases in efficiency due to lower step counts and smaller waste streams, because reaction sites no longer need to be preactivated with functional groups in order to obtain a selective reaction. As a consequence, the number of substrates for oxidative activation is intrinsically larger than for non-oxidative coupling processes. The challenge in this area follows from this fact, namely selectivity in any given transformation due the numerous C-H bonds present in a typical organic molecule. Use of biomimetic processes leads to bioactive natural products and natural product-like cores, desirable entities in medicinal chemistry. New synthetic methods greatly increase access to untapped chemical space, leading to materials and pharmaceuticals that benefit society. Invaluable training, absent outside of industrial settings, will be afforded to graduate students and other coworkers.